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The Discovery of Small Allosteric and Active Site Inhibitors of the SARS-CoV-2 Main Protease via Structure-Based Virtual Screening and Biological Evaluation.
Mahgoub, Radwa E; Mohamed, Feda E; Alzyoud, Lara; Ali, Bassam R; Ferreira, Juliana; Rabeh, Wael M; AlNeyadi, Shaikha S; Atatreh, Noor; Ghattas, Mohammad A.
  • Mahgoub RE; College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates.
  • Mohamed FE; AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 64141, United Arab Emirates.
  • Alzyoud L; Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 15551, United Arab Emirates.
  • Ali BR; College of Pharmacy, Al Ain University, Abu Dhabi 64141, United Arab Emirates.
  • Ferreira J; AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 64141, United Arab Emirates.
  • Rabeh WM; Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 15551, United Arab Emirates.
  • AlNeyadi SS; Zayed Centre for Health Sciences, United Arab Emirates University, Al-Ain 15551, United Arab Emirates.
  • Atatreh N; Science Division, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates.
  • Ghattas MA; Science Division, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates.
Molecules ; 27(19)2022 Oct 09.
Article in English | MEDLINE | ID: covidwho-2066287
ABSTRACT
The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the Mpro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with Ki values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Journal subject: Biology Year: 2022 Document Type: Article Affiliation country: Molecules27196710

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Journal subject: Biology Year: 2022 Document Type: Article Affiliation country: Molecules27196710